Indoles cinnolines

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

Quinoline 1-oxides can be rearranged photochemically into indoles (103 — 104 — 105) or N-hydroxyindoles (106 — 107). Cinnolines are reductively ring-contracted into indoles (Section 3.2.1.6.9.ii). 

Other ring types prepared from thioureas include those of Petersen and Hcitzer, who prepared the naphthoxathiolones 233 (X = 0, Y = OH)411 from 2-(2-methylpropanal-2-yl)-l,4-naphthoquinone and 233 (X = NH, Y = H)412 starting with a tctrahydrobenz[gr]indol-5-one, each through reaction with thiourea in hydrochloric acid. Kaushal and Narang413 prepared a series of dihydrothiazolo[4,5-c]cinnolines... 

Oxazines, which are readily prepared from enamines and a-bromokctoximes, are reductively converted to pyrroles in good yields by iron carbonyls (Scheme 116) (81CL869). The reductive conversion of cinnolines to indoles or indolines (71JCS(C)3088> and of phthalazines to isoindoles or phthalimidines (70ACS1867) may occasionally be of synthetic value. 

A Suzuki coupling of 5-chloro-2-methyl-6-phenyl-2H-pyridazin-3-one (10) ultimately led to diazino-fused indole 11 and cinnoline 12 and allowed access to a novel pyrimidoisoquinoline ring system in a one-pot fashion <02T10137>. Mn(II)-azido networks of the type [Mn(N3)2(L)] like 13 with new 3-D topologies were obtained using both pyridazine and pyrimidine ligands <02CC64>. 

Chloroperoxidase catalysis by, 58, 302 in chlorination of pyrazoles, 57, 337 Chlorophyll, thioaldehyde synthetic intermediate to, 55, 3 Chlorosulfonyl isocyanate, reaction with 2-arylhydrazono-3-oxobutanoate, 59, 148 Chromatography, of [l,2,4]triazolo[l,5-a]-pyrimidines, 57, 106 Chrom-3-enes, see 2//-l-Benzopyrans Chromium tricarbonyl complexes of 3,5-diphenyl-l-(alkyl- or oxido-)-thiabenzenes, 59, 206, 227 indoles, lithiation of, 56, 181, 184 of pyridine, 58, 160 pyridines, lithiation of, 56, 230, 239 of 2f/-thiopyrans, 59, 227 Chromones, see l-Benzopyran-4-ones Cinnamonitrile, a-cyano-, condensations with thio-, seleno-amides, 59, 184, 186 Cinnoline, nitration, MO calculation, 59, 302... 

Diazotization of 4-amino-5-alkynylpyrazole 335 followed by intramolecular cyclization gave 7-chloro-17/-pyr-azolo[4,3-f]pyridazines 336 the amino and alkynyl positional isomers at the C-3 and C-4 positions were also cyclized to give other pyrazolopyridazines (Equation 64) <1998F1C0519>. Diazotization of 4-aryl-5-aminopyrazoles (aryl = 4,5-dimethoxyphenyl and indol-3-yl) followed by intramolecular azo coupling reactions led to the corresponding pyrazolo[3,4-f]cinnolines or pyrazolo[3, 4 6,5]pyridazino[3,4-. ]indoles <2004CHE1506>. 

Reduction of the (benzo)pyridazine derivatives was not discussed in CHEC-I, but reduction of these systems is known to occur readily. Cleavage of the N—N bonds can occur, in addition to hydrogenation of the ring, to give open chain products (e.g., tetramethylenediamine from pyridazine) which may re-cyclize (e.g., to give indoles from cinnolines). Examples of work from the current review period are given below. 

Reduction of 5- and 8-nitrocinnolines with zinc amalgam in aqueous acetic acid gives the corresponding 4- and 7-amino-indoles these conditions have previously been used to effect ring-contraction of 4-alkyl- and 4-aryl-cinnolines. Treatment of the perhydropyridazine (95) with hot concentrated sulphuric acid results in nearly quantitative rearrangement to the pyrazole (96). ... 

Reaction of the carbanion 222 results in the formation of the acetophenone ylid 223, which on treatment with acids or nitrosobenzene is converted to the indole derivatives 224 or 225. Ring closure of 223 with orthoesters yields the quinolones 226 - with carbon disulfide 227 is obtained (Scheme 38). Treatment of lA with dimsyl sodium (228) leads to 229, from which with aldehydes the quinolinones 231 are obtained. Reaction with HNO2 leads to the cinnoline 232, and with carboxy-... 

Aza-heterocycle Ring Contraction. A variety of polyaza six-ring heterocycles undergo contraction with formal excision of N, e.g. eq 14. Further heteroatoms in the ring are tolerated 1,2,3-triazines yield pyrazoles and 1,2,4-triazines yield imidazoles, with the latter usually requiring reflux temperature. The utility of indole syntheses from cinnolines " by this method should be noted. Adj acency of heteroatoms is not required conversions of pyrimidine to pyrrole and 1,3,5-triazine to imidazole have been recorded. The mechanism of these conversions is unclear, but ring dihydro derivatives are thought to be involved. 

---